The role of extracellular vesicles (EVs) in mediating the immunosuppressory properties of mesenchymal stem cells (MSCs) has recently attracted remarkable scientific interest. The aim of this work was to analyze the transport mechanisms of membrane and cytoplasmic components between T lymphocytes and adipose tissue-derived MSCs (AD-MSCs), by focusing on the role of distinct populations of EVs, direct cell–cell contacts, and the soluble mediators per se in modulating T lymphocyte function. We found that neither murine thymocytes and human primary T cells nor Jurkat lymphoblastoid cells incorporated appreciable amounts of MSC-derived microvesicles (MVs) or exosomes (EXOs). Moreover, these particles had no effect on the proliferation and IFN-γ production of in vitro-stimulated primary T cells. In contrast, AD-MSCs incorporated large amounts of membrane components from T cells as an intensive uptake of EXOs and MVs could be observed. Interestingly, we found a bidirectional exchange of cytoplasmic components between human AD-MSCs and primary T lymphocytes, mediated by tunneling nanotubes (TNTs) derived exclusively from the T cells. In contrast, TNTs couldn't be observed between AD-MSCs and the Jurkat cells. Our results reveal a novel and efficient way of intercellular communication between MSCs and T cells, and may help a better understanding of the immunomodulatory function of MSCs.
Get full access to this article
View all access options for this article.
References
1.
MorrisonSJ and ScaddenDT. (2014). The bone marrow niche for haematopoietic stem cells. Nature, 505:327–334.
2.
Abu KasimNH, GovindasamyV, GnanasegaranN, MusaS, PradeepPJ, SrijayaTC and AzizZACA. (2012). Unique molecular signatures influencing the biological function and fate of post-natal stem cells isolated from different sources. J Tissue Eng Regen Med, 9:E252–E266.
3.
PittengerMF, MackayAM, BeckSC, JaiswalRK, DouglasR, MoscaJD, MoormanMA, SimonettiDW, CraigS and MarshakDR. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284:143–147.
4.
StoltzJF, de IslaN, LiYP, BensoussanD, ZhangL, HuselsteinC, ChenY, DecotV, MagdalouJ, et al. (2015). Stem Cells and Regenerative Medicine: myth or reality of the 21th century. Stem Cells Int, 2015:734731.
5.
SunLY, WangDD, LiangJ, ZhangHY, FengXB, WangH, HuaBZ, LiuBJ, YeSQ, et al. (2010). Umbilical Cord Mesenchymal Stem Cell Transplantation in Severe and Refractory Systemic Lupus Erythematosus. Arthritis Rheum, 62:2467–2475.
6.
NardiNB. (2014). Therapeutic potential of mesenchymal stem cells in regenerative medicine. Int J Mol Med, 34:S11–S11.
7.
GaoF, ChiuSM, MotanDA, ZhangZ, ChenL, JiHL, TseHF, FuQL and LianQ. (2016). Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis, 7:e2062.
8.
AggarwalS and PittengerMF. (2005). Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 105:1815–1822.
9.
Castro-ManrrezaME and MontesinosJJ. (2015). Immunoregulation by Mesenchymal Stem Cells: biological aspects and clinical applications. J Immunol Res, 2015:394917.
10.
FontaineMJ, ShihH, SchaeferR and PittengerMF. (2016). Unraveling the mesenchymal stromal cells' paracrine immunomodulatory effects. Transfus Med Rev, 30:37–43.
11.
Fajka-BojaR, UrbanVS, SzebeniGJ, CzibulaA, BlaskoA, Kriston-PalE, MakraI, HornungA, SzaboE, et al. (2016). Galectin-1 is a local but not systemic immunomodulatory factor in mesenchymal stromal cells. Cytotherapy, 18:360–370.
12.
ShengHM, WangY, JinYQ, ZhangQY, ZhangY, WangL, ShenB, YinS, LiuW, CuiL and LiNL. (2008). A critical role of IFN gamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res, 18:846–857.
13.
XueQ, LuanXY, GuYZ, WuHY, ZhangGB, YuGH, ZhuHT, WangMY, DongWL, GengYJ and ZhangXG. (2010). The negative co-signaling molecule B7-H4 is expressed by human bone marrow-derived mesenchymal stem cells and mediates its T-cell modulatory activity. Stem Cells Dev, 19:27–37.
NaT, LiuJ, ZhangKH, DingM and YuanBZ. (2015). The notch signaling regulates CD105 expression, osteogenic differentiation and immunomodulation of human umbilical cord mesenchymal stem cells. Plos One, 10:e0118168.
16.
Gur-WahnonD, BorovskyZ, BeythS, LiebergallM and RachmilewitzJ. (2007). Contact-dependent induction of regulatory antigen-presenting cells by human mesenchymal stem cells is mediated via STAT3 signaling. Exp Hematol, 35:426–433.
17.
SimonsM and RaposoG. (2009). Exosomes—vesicular carriers for intercellular communication. Curr Opin Cell Biol, 21:575–581.
18.
GreeningDW, GopalSK, XuR, SimpsonRJ and ChenW. (2015). Exosomes and their roles in immune regulation and cancer. Semin Cell Dev Biol, 40:72–81.
19.
TheryC, OstrowskiM and SeguraE. (2009). Membrane vesicles as conveyors of immune responses. Nat Rev Immunol, 9:581–593.
20.
LotvallJ, HillAF, HochbergF, BuzasEI, Di VizioD, GardinerC, GhoYS, KurochkinIV, MathivananS, et al. (2014). Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles, 3:26913.
21.
KatsudaT, KosakaN, TakeshitaF and OchiyaT. (2013). The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. Proteomics, 13:1637–1653.
22.
BaglioSR, PegtelDM and BaldiniN. (2012). Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front Physiol, 3:359.
23.
Yanez-MoM, SiljanderPRM, AndreuZ, ZavecAB, BorrasFE, BuzasEI, BuzasK, CasalE, CappelloF, et al. (2015). Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles, 4:27066
GordonD, PavlovskaG, UneyJB, WraithDC and ScoldingNJ. (2010). Human mesenchymal stem cells infiltrate the spinal cord, reduce demyelination, and localize to white matter lesions in experimental autoimmune encephalomyelitis. J Neuropathol Exp Neurol, 69:1087–1095.
26.
HanC, SunX, LiuL, JiangH, ShenY, XuX, LiJ, ZhangG, HuangJ, et al. (2016). Exosomes and their therapeutic potentials of stem cells. Stem Cells Int, 2016:7653489.
27.
GyorgyB, ModosK, PallingerE, PalocziK, PasztoiM, MisjakP, DeliMA, SiposA, SzalaiA, et al. (2011). Detection and isolation of cell-derived microparticles are compromised by protein complexes resulting from shared biophysical parameters. Blood, 117:E39–E48.
28.
de VrijJ, MaasSLN, van NispenM, Sena-EstevesM, LimpensRWA, KosterAJ, LeenstraS, LamfersML and BroekmanMLD. (2013). Quantification of nanosized extracellular membrane vesicles with scanning ion occlusion sensing. Nanomedicine, 8:1443–1458.
29.
LacroixR, JudiconeC, MooberryM, BoucekineM, KeyNS, Dignat-GeorgeF and IS Workshop. (2013). Standardization of pre-analytical variables in plasma microparticle determination: results of the International Society on Thrombosis and Haemostasis SSC Collaborative workshop. J Thromb Haemost, 11:1190–1193.
30.
RaposoG and StoorvogelW. (2013). Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol, 200:373–383.
31.
DangS, YuZM, ZhangCY, ZhengJ, LiKL, WuY, QianLL, YangZY, LiXR, ZhangY and WangRX. (2015). Autophagy promotes apoptosis of mesenchymal stem cells under inflammatory microenvironment. Stem Cell Res Ther, 6:247.
32.
MaS, XieN, LiW, YuanB, ShiY and WangY. (2014). Immunobiology of mesenchymal stem cells. Cell Death Differ, 21:216–225.
33.
BernardoME and FibbeWE. (2013). Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell, 13:392–402.
34.
de CandiaP, De RosaV, CasiraghiM and MatareseG. (2016). Extracellular RNAs: a secret arm of immune system regulation. J Biol Chem, 291:7221–7228.
35.
GyorgyB, SzaboTG, PasztoiM, PalZ, MisjakP, AradiB, LaszloV, PallingerE, PapE, et al. (2011). Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci, 68:2667–2688.
36.
BrunoS, GrangeC, DeregibusMC, CalogeroRA, SaviozziS, CollinoF, MorandoL, BuscaA, FaldaM, et al. (2009). Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol, 20:1053–1067.
37.
CollinoF, DeregibusMC, BrunoS, SterponeL, AghemoG, ViltonoL, TettaC and CamussiG. (2010). Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. Plos One, 5:e11803.
38.
LaiRC, TanSS, TehBJ, SzeSK, ArslanF, de KleijnDP, ChooA and LimSK. (2012). Proteolytic Potential of the MSC Exosome Proteome: implications for an exosome-mediated delivery of therapeutic proteasome. Int J Proteomics, 2012:971907.
39.
SimpsonRJ, KalraH and MathivananS. (2012). ExoCarta as a resource for exosomal research. J Extracell Vesicles, 1:18374.
FierabracciA, Del FattoreA, LucianoR, MuracaM, TetiA and MuracaM. (2015). Recent advances in mesenchymal stem cell immunomodulation: the role of microvesicles. Cell Transplant, 24:133–149.
42.
BrunoS, DeregibusMC and CamussiG. (2015). The secretome of mesenchymal stromal cells: role of extracellular vesicles in immunomodulation. Immunol Lett, 168:154–158.
43.
McCoy-SimandleK, HannaSJ and CoxD. (2016). Exosomes and nanotubes: control of immune cell communication. Int J Biochem Cell Biol, 71:44–54.
44.
BlazquezR, Sanchez-MargallolFM, de la RoseO, DalemansW, AlvarezV, TarazoneR and CasadolJG. (2014). Immunomodulatory potential of human adipose mesenchymal stem cells derived exosomes on in vitro stimulated T cells. Front Immunol, 5:556.
45.
BudoniM, FierabracciA, LucianoR, PetriniS, Di CiommoV and MuracaM. (2013). The immunosuppressive effect of mesenchymal stromal cells on B lymphocytes is mediated by membrane vesicles. Cell Transplant, 22:369–379.
46.
ConfortiA, ScarsellaM, StarcN, GiordaE, BiaginiS, ProiaA, CarsettiR, LocatelliF and BernardoME. (2014). Microvescicles derived from mesenchymal stromal cells are not as effective as their cellular counterpart in the ability to modulate immune responses in vitro. Stem Cells Dev, 23:2591–2599.
47.
MokarizadehA, DelirezhN, MorshediA, MosayebiG, FarshidA-A and MardaniK. (2012). Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling. Immunol Lett, 147:47–54.
48.
ZhangB, YinY, LaiRC, TanSS, ChooABH and LimSK. (2014). Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev, 23:1233–1244.
49.
ChoJA, ParkH, LimEH and LeeKW. (2012). Exosomes from breast cancer cells can convert adipose tissue-derived mesenchymal stem cells into myofibroblast-like cells. Int J Oncol, 40:130–138.
50.
DavisDM and SowinskiS. (2008). Membrane nanotubes: dynamic long-distance connections between animal cells. Nat Rev Mol Cell Biol, 9:431–436.
51.
SowinskiS, JollyC, BerninghausenO, PurbhooMA, ChauveauA, KoehlerK, OddosS, EissmannP, BrodskyFM, et al. (2008). Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV-1 transmission. Nat Cell Biol, 10:211–219.
52.
FigeacF, LesaultPF, Le CozO, DamyT, SouktaniR, TrebeauC, SchmittA, RibotJ, MounierR, et al. (2014). Nanotubular crosstalk with distressed cardiomyocytes stimulates the paracrine repair function of mesenchymal stem cells. Stem Cells, 32:216–230.
53.
BaiL, LennonDP, EatonV, MaierK, CaplanAI, MillerSD and MillerRH. (2009). Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia, 57:1192–1203.
54.
ImbertiB, MorigiM and BenigniA. (2011). Potential of mesenchymal stem cells in the repair of tubular injury. Kidney Int Suppl, 1:90–93.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
